Malaria remains an extremely important worldwide problem, but current therapies are limited by drug resistance and toxicity, and new drugs are urgently needed. Falcipain, a cysteine protease found in Plasmodium falciparum trophozoites, is required for hemoglobin degradation and development by erythrocytic parasites, and thus is a promising chemotherapeutic target. In this project we will use established Corvas technologies to design and synthesize new falcipain inhibitors. A new model of the three dimensional structure of falcipain will be made based on available cognate structures. Transition-state mimic inhibitors of falcipain will be rationally designed using this structure. Focused libraries of the designed inhibitors and their analogs will be synthesized using Corvas's proprietary technologies for solid phase peptide synthesis of compounds incorporating transition state mimics. Compounds found to be potent falcipain inhibitors will be screened for activity against cultured P. falciparum and, for selected compounds, for efficacy against murine malaria. Additionally, we will express falcipain in a heterologous system to provide enzyme for subsequent structural studies. The Phase I studies described in this proposal should identify potent falcipain inhibitors and provide the groundwork for additional studies, planned for Phase II, to optimize Corvas falcipain inhibitors and evaluate these compounds as antimalarial drugs. PROPOSED COMMERCIAL APPLICATIONS: The need for new antimalarial drugs for prophylaxis and therapy is great, with increasing resistance to current therapy by the most lethal and debilitating malarial parasite, P. falciparum. The World Health Organization and U.S. Department of Defense has previously helped to develop potential antimalarial drugs and may be willing to do so again, in the interest of the populations most likely to benefit.